title: The NADPH metabolic network regulates human αB-crystallin cardiomyopathy and reductive stress in Drosophila melanogaster.
abstract: Dominant mutations in the alpha-B crystallin (CryAB) gene are responsible for a number of inherited human disorders, including cardiomyopathy, skeletal muscle myopathy, and cataracts. The cellular mechanisms of disease pathology for these disorders are not well understood. Among recent advances is that the disease state can be linked to a disturbance in the oxidation/reduction environment of the cell. In a mouse model, cardiomyopathy caused by the dominant CryAB(R120G) missense mutation was suppressed by mutation of the gene that encodes glucose 6-phosphate dehydrogenase (G6PD), one of the cell's primary sources of reducing equivalents in the form of NADPH. Here, we report the development of a Drosophila model for cellular dysfunction caused by this CryAB mutation. With this model, we confirmed the link between G6PD and mutant CryAB pathology by finding that reduction of G6PD expression suppressed the phenotype while overexpression enhanced it. Moreover, we find that expression of mutant CryAB in the Drosophila heart impaired cardiac function and increased heart tube dimensions, similar to the effects produced in mice and humans, and that reduction of G6PD ameliorated these effects. Finally, to determine whether CryAB pathology responds generally to NADPH levels we tested mutants or RNAi-mediated knockdowns of phosphogluconate dehydrogenase (PGD), isocitrate dehydrogenase (IDH), and malic enzyme (MEN), the other major enzymatic sources of NADPH, and we found that all are capable of suppressing CryAB(R120G) pathology, confirming the link between NADP/H metabolism and CryAB.
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, Utah, USA.
authors.forename: Heng B
authors.initials: HB
authors.lastname: Xie
authors.forename: Anthony
authors.initials: A
authors.lastname: Cammarato
authors.forename: Namakkal S
authors.initials: NS
authors.lastname: Rajasekaran
authors.forename: Huali
authors.initials: H
authors.lastname: Zhang
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Suggs
authors.forename: Ho-Chen
authors.initials: HC
authors.lastname: Lin
authors.forename: Sanford I
authors.initials: SI
authors.lastname: Bernstein
authors.forename: Ivor J
authors.initials: IJ
authors.lastname: Benjamin
authors.forename: Kent G
authors.initials: KG
authors.lastname: Golic
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002386:Cataract / Q000235:genetics / Q000473:pathology; D004331:Drosophila melanogaster / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D008291:Malate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D051379:Mice; D009135:Muscular Diseases / Q000235:genetics / Q000473:pathology; D020125:Mutation, Missense; D009249:NADP / Q000235:genetics / Q000378:metabolism*; D010734:Phosphogluconate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D038203:alpha-Crystallin B Chain / Q000235:genetics* / Q000378:metabolism
chemical_list: C059215:CRYAB protein, human; D038203:alpha-Crystallin B Chain; D009249:NADP; D008291:Malate Dehydrogenase; D007521:Isocitrate Dehydrogenase; D010734:Phosphogluconate Dehydrogenase; D005954:Glucosephosphate Dehydrogenase